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Neoadjuvant chemotherapy is associated with an altered metabolic profile and increased cancer stemness in patients with pancreatic ductal adenocarcinoma
Molecular Oncology ( IF 5.0 ) Pub Date : 2022-11-18 , DOI: 10.1002/1878-0261.13344 Manoj Amrutkar 1, 2 , Caroline S Verbeke 1, 3 , Anette Vefferstad Finstadsveen 1 , Linda Dorg 3 , Knut Jørgen Labori 4, 5 , Ivar P Gladhaug 4, 5
Molecular Oncology ( IF 5.0 ) Pub Date : 2022-11-18 , DOI: 10.1002/1878-0261.13344 Manoj Amrutkar 1, 2 , Caroline S Verbeke 1, 3 , Anette Vefferstad Finstadsveen 1 , Linda Dorg 3 , Knut Jørgen Labori 4, 5 , Ivar P Gladhaug 4, 5
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The modest clinical benefits of neoadjuvant chemotherapy (NAT) in pancreatic ductal adenocarcinoma (PDAC) are associated with a lack of robust data on treatment-induced changes in the tumor. To this end, comparative proteomic profiling of tumor tissue samples from treatment-naïve (TN, n = 20) and NAT-treated (n = 22) PDACs was performed. Differentially expressed proteins were identified and correlation with overall survival (OS) was performed. Tumors were also examined for histopathological changes and expression of cancer stem cell (CSC) markers. Serum from 33 matched patients was analyzed for metabolic markers. Cytotoxicity, proliferation, and expression of CSC markers were assessed in chemoresistant Panc-1 and Mia PaCa-2 cells. Of the 2265 proteins identified, 227 and 144 proteins showed significantly altered expression and differential phosphorylation, respectively, in NAT compared with TN samples. The majority of these were metabolism-related proteins, and 14 of these correlated moderately with OS. NAT-treated tumors and chemoresistant cancer cells showed increased expression of CSC markers. Serum ALDH1A1 was higher in NAT compared with TN. Differentially phosphorylated proteins were mainly involved in cytoskeleton organization, cell locomotion, motility, and migration, and 17 of these showed a strong positive correlation with OS. This study provides evidence of the effects of NAT on PDAC metabolism at both the tumor and the systemic levels. NAT-treated tumors showed significantly lower expression of metabolic proteins, and patients who underwent NAT showed reduced serum lactate and high-density lipoprotein-cholesterol. Lastly, cancer cells that survived cytotoxic treatment expressed higher CSC markers, both in vivo and in vitro.
中文翻译：
新辅助化疗与胰腺导管腺癌患者的代谢特征改变和癌症干细胞增加相关
新辅助化疗（NAT）在胰腺导管腺癌（PDAC）中的临床获益有限，与治疗引起的肿瘤变化缺乏可靠的数据有关。为此，对来自未接受治疗的 PDAC（TN， n = 20）和经过 NAT 处理的 PDAC（ n = 22）的肿瘤组织样本进行了比较蛋白质组学分析。鉴定出差异表达的蛋白质并进行与总生存期（OS）的相关性。还检查了肿瘤的组织病理学变化和癌症干细胞（CSC）标记物的表达。对 33 名匹配患者的血清进行了代谢标志物分析。在化疗耐药的 Panc-1 和 Mia PaCa-2 细胞中评估了 CSC 标记物的细胞毒性、增殖和表达。在鉴定的 2265 个蛋白质中，与 TN 样品相比，NAT 样品中分别有 227 个和 144 个蛋白质显示出显着改变的表达和差异磷酸化。其中大部分是代谢相关蛋白，其中 14 个与 OS 中度相关。 NAT 处理的肿瘤和化疗耐药癌细胞显示 CSC 标志物表达增加。 NAT 组血清 ALDH1A1 高于 TN 组。差异磷酸化蛋白主要参与细胞骨架组织、细胞运动、运动和迁移，其中17个与OS呈强正相关。这项研究提供了 NAT 对肿瘤和全身水平 PDAC 代谢影响的证据。 NAT 治疗的肿瘤显示代谢蛋白的表达显着降低，接受 NAT 的患者血清乳酸和高密度脂蛋白胆固醇降低。 最后，在细胞毒治疗中幸存的癌细胞在体内和体外都表达了更高的 CSC 标志物。
更新日期：2022-11-18
中文翻译：
新辅助化疗与胰腺导管腺癌患者的代谢特征改变和癌症干细胞增加相关
新辅助化疗（NAT）在胰腺导管腺癌（PDAC）中的临床获益有限，与治疗引起的肿瘤变化缺乏可靠的数据有关。为此，对来自未接受治疗的 PDAC（TN， n = 20）和经过 NAT 处理的 PDAC（ n = 22）的肿瘤组织样本进行了比较蛋白质组学分析。鉴定出差异表达的蛋白质并进行与总生存期（OS）的相关性。还检查了肿瘤的组织病理学变化和癌症干细胞（CSC）标记物的表达。对 33 名匹配患者的血清进行了代谢标志物分析。在化疗耐药的 Panc-1 和 Mia PaCa-2 细胞中评估了 CSC 标记物的细胞毒性、增殖和表达。在鉴定的 2265 个蛋白质中，与 TN 样品相比，NAT 样品中分别有 227 个和 144 个蛋白质显示出显着改变的表达和差异磷酸化。其中大部分是代谢相关蛋白，其中 14 个与 OS 中度相关。 NAT 处理的肿瘤和化疗耐药癌细胞显示 CSC 标志物表达增加。 NAT 组血清 ALDH1A1 高于 TN 组。差异磷酸化蛋白主要参与细胞骨架组织、细胞运动、运动和迁移，其中17个与OS呈强正相关。这项研究提供了 NAT 对肿瘤和全身水平 PDAC 代谢影响的证据。 NAT 治疗的肿瘤显示代谢蛋白的表达显着降低，接受 NAT 的患者血清乳酸和高密度脂蛋白胆固醇降低。 最后，在细胞毒治疗中幸存的癌细胞在体内和体外都表达了更高的 CSC 标志物。
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